Meyerowitz EA, et al. FASEB Journal. 2020;doi:10.1096/fj.202000919.
A 'triumph of hope over facts': The rise and fall of hydroxychloroquine for COVID-19
The rise and fall of chloroquine and hydroxychloroquine as “game-changing” treatments for COVID-19 should come as no surprise to experts who have paid attention to the history of these drugs, according to findings published in The FASEB Journal.
Mark C. Poznansky, MD, PhD, director of the vaccine and immunotherapy center at Massachusetts General Hospital, associate professor of medicine at Harvard Medical School and attending physician in infectious diseases medicine at Massachusetts General Hospital, and colleagues, combed through the literature in search of rationale for using hydroxychloroquine in the setting of an acute severe viral respiratory infection.
Their results showed that hydroxychloroquine impacts cytokine production and suppresses antigen presentation in a way that potentially undermines the adaptive antiviral immune response to COVID-19. While hydroxychloroquine has, in fact, shown in vitro efficacy against other respiratory virus infections, the in vivo data tell a different story.
Poznansky and colleagues initiated their research as hydroxychloroquine began to be used more widely in patients with moderate and severe disease in the context of the early weeks of the pandemic. Their review was published after President Donald J. Trump had promoted the drug as a potentially curative agent for COVID-19, and as more data emerged showing that prophylactic and pharmacotherapeutic use were unlikely to be effective.
Healio Rheumatology spoke with Poznansky to discuss the history, the science and the politics of chloroquine and hydroxychloroquine in the COVID-19 setting.
Q: Why were chloroquine/hydroxychloroquine originally considered promising candidates for COVID-19 prophylaxis?
Poznansky: It was the convergence of a couple factors. One was that there were preliminary data from small studies in China and France suggesting that hydroxychloroquine could be useful in treating COVID-19. It is important to note that the French study was subsequently questioned by the publisher and did not meet the standards of the International Journal of Anti-Microbial Agents.
The other factor is that there is an interest in repurposing chloroquine and hydroxychloroquine as panacea type drugs as has happened with previous epidemics. It has been tried a number of times, with influenza and with Ebola. But each time it didn’t work. It is obviously effective in malaria, lupus and rheumatoid arthritis, but it has not panned out in any of these other emergency situations.
Q: Why do people keep trying it in these outbreaks if history has shown that it rarely works?
Poznansky: It probably has a lot to do with the cycle of human memory more than anything else. If you were to take a deep look into the history of medicine, I am certain you would see how many different treatments and approaches come up in cycles every 10 or 20 years. Hydroxychloroquine is definitely part of that ‘Groundhog Day’ cycle.
Q: Could it have to do with the fact that lupus, malaria and rheumatoid arthritis are a wide and disparate range of conditions?
Poznansky: The fact that it is an effective and widely used prophylactic agent in malaria makes it feel like it is very safe. But you have to look at the whole picture. If I had a patient coming in to get hydroxychloroquine to prevent malaria on a safari trip to Kenya, and then they suddenly developed a rip-roaring respiratory infection, I would tell them two things: one, you are not getting any hydroxychloroquine because it may suppress your immune system and your ability to fight the infection; and two, you are not going on any safari until you recover.
In the current scenario, there are just too many unknowns about what will happen to the virus or viral load of COVID-19 with the immune suppression associated with hydroxychloroquine to administer this drug outside of carefully controlled clinical trials.
Q: Have these two drugs been used effectively before to treat respiratory viruses?
Poznansky: As far as I know and at the time of review, they have not.
Q: How did anecdotal evidence and limited drug trials contribute to the popular consideration for these drugs for COVID-19?
Poznansky: The biggest evidence was in vitro data showing that it works in respiratory viruses. Unfortunately, you can see all kinds of reactions in vitro that do not have any direct relationship to what happens in vivo. That is why antiviral drug development is difficult.
Q: Prior to President Trump’s endorsement during a press briefing, were these drugs considered the most promising candidates?
Poznansky: Well, again, there was the old chestnut of hydroxychloroquine as a cure-all being circulated around. That was percolating in the ether. Then there is the triumph of hope and anecdotal reports over facts. We then saw a growing storm of patients with COVID-19 being admitted into the hospitals and overwhelming the system. Intensive care doctors did everything they could in terms of supportive care, with respiratory support and organ support, but they had nothing that could directly treat the infection.
So, the question was raised: Is there anything that we can do to prevent patients with COVID from getting sicker? That is what led, in part, to us betting on hope and anecdotal reports. Obviously as data on this accumulated, much of which we reviewed, our enthusiasm for this approach was tempered.
Q: Based on your review, does the immunosuppressive element of these drugs benefit or inhibit defense against COVID-19?
Poznansky: As we dug through the literature in the preliminary stages of thinking about this article, this is where the idea of hope over reality was striking. This is what prompted my colleagues and I to put this article together very quickly. The immunosuppressive nature of these drugs was embedded in the literature quite deeply.
We now have multiple ways of suppressing the immune system, but the way it happens with hydroxychloroquine may make it especially risky for patients with an acute viral respiratory infection. It has the potential to suppress and take apart elements of antiviral immunity. This is not what you want to be reading in the context of COVID-19, and it was all right there in the scientific literature.
Q: This is alarming. Are people still using it?
Poznansky: Yes, but within the context of strictly controlled clinical trials. This was the point we were trying to emphasize. Outside of clinical trials, the risk of hydroxychloroquine for some patients with other underlying factors could be greater than the benefit.
We acknowledge that there may be a role for this drug in COVID-19. However, you need to consider the patient’s medical history and be able to monitor viral load so you are not just allowing for the possibility of uncontrolled viral replication. That said, we acknowledge that some patients with lupus or rheumatoid arthritis who were taking hydroxychloroquine did not have higher rates of respiratory viral infections, even after using the drug for 6 months. It is a relevant scientific point.
Q: So, there may, in fact, be a role for hydroxychloroquine after all is said and done?
Poznansky: Correct. It is a refined medical point. There may be a time and a place for this drug in COVID-19. But it is important to understand that looking at it within the context of a clinical trial is the way to gather this information. Clinical trials will help us understand what kind of patient might benefit from these drugs and at what stages of the infection. There are also clinical studies that are looking at the potential prophylactic benefit of this drug in preventing COVID infections.
Q: But if there are such red flags linked to hydroxychloroquine in this type of viral infection, given that time is short and resources are scarce, wouldn’t it be better to be doing clinical trials of other approaches and medications?
Poznansky: This is a good point. A patient cannot be in two clinical trials at the same time. But, if there was a better immune modulator or a better antiviral drug available, then one would have to weigh things up.
Q: Are there any other aspects of COVID-19 you would like to address?
Poznansky: The biggest concept to consider is this thing called scientific rationale; or, in this context, the data-informed reasons for doing new things in medicine. As this pandemic was developing, we had the time, although very limited, to look at the scientific rationale for the therapies we were using. Some evidence for hydroxychloroquine suppressing antiviral response was there in the literature. But with no other options, we went for hope and anecdotal reports.
Going forward, we have to be smarter about applying new drugs to this condition. And when we see problems developing, we have to correct our approach faster. We need to make sure we are following that key guiding light in medicine of doing no harm.
Q: This seems self-evident.
Poznansky: The medical community, along with governing bodies, developed clinical trials to avoid this exact scenario. The clinical trial process was developed to maximize our knowledge, to maximize our understanding of the risks and benefits of the experimentally-tested drugs for the benefit of our patients.
Meyerowitz EA, et al. FASEB Journal. 2020;doi:10.1096/fj.202000919.
For more information:
Mark C. Poznansky, MD, PhD, can be reached at The Vaccine and Immunotherapy Center, MGH (east), Charlestown Navy Yard. MA 02129; email: email@example.com.